tbuckley/cabot-search huggingface dataset:
Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres Followed by Gemcitabine plus Cisplatin for Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Single-Arm Multicenter Clinical Trial
Authors: Stephen Lam Chan, Chanisa Chotipanich, Su Pin Choo, Su Wen Kwang, Frankie Mo, Akeanong Worakitsitisatorn, David Tai, Raghav Sundar, David Chee Eng Ng, Kelvin Siu Hoong Loke, Leung Li, Kelvin Kwok Chai Ng, Yong Wei Peng, Simon Chun-Ho Yu
Journal: Liver Cancer (2022)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; This investigator-initiated clinical trial aims to study the efficacy and safety of administering selective internal radiation therapy with resin yttrium-90 microspheres (SIRT) followed by standard chemotherapy in unresectable intrahepatic cholangiocarcinoma (ICC). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A phase 2 single-arm multicenter study was conducted in patients with unresectable ICC (NCT02167711). SIRT was administered at dose of 120 Gy targeted at tumor followed by commencement of gemcitabine 1,000 mg/m&lt;sup&gt;2&lt;/sup&gt; and cisplatin 25 mg/m&lt;sup&gt;2&lt;/sup&gt; on days one and eight of a 21-day cycle. The primary endpoint was overall survival (OS), and the secondary endpoints include progression-free survival (PFS), response rate according to Response Evaluation Criteria in solid tumors 1.1, toxicity, and time from SIRT to commencement of chemotherapy. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Total 31 patients were screened and twenty-four were recruited. All patients completed SIRT and 16 of them underwent subsequent chemotherapy. The median cycle of chemotherapy was 5 (range: 1–8). The median OS was 13.6 months (95% CI: 5.4–21.6) for the intent-to-treat population. Among 16 patients undergoing chemotherapy, the median OS was 21.6 months (95% CI: 7.3–25.2) and the median PFS was 9 months (95% CI: 3.2–13.1). The response rate was 25% (95% CI: 3.8–46.2%), and the disease control rate was 75% (95% CI: 53.8–96.2%). No new safety signal was observed, with fewer than 10% of patients suffering from grade 3 or higher treatment-related adverse events. The median time from SIRT to chemotherapy was 29 (range: 7–42) days. Eight patients could not receive chemotherapy due to rapid progressive disease (&lt;i&gt;n&lt;/i&gt; = 4), underlying treatment unrelated comorbidities (&lt;i&gt;n&lt;/i&gt; = 2), and withdrawal of consent due to personal reasons (&lt;i&gt;n&lt;/i&gt; = 2). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Treatment of SIRT followed by standard gemcitabine and cisplatin chemotherapy is feasible and effective for unresectable ICC. Further studies are required to study the optimal sequence of SIRT and chemotherapy.
Ergonomics for Surgeons by Surgeons—Posture, Loupes, and Exercise
Authors: Pouya Hemmati, Tom C. Nguyen, Joseph A. Dearani
Journal: JAMA Surgery (2022)

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Abstract 3068: Identify targetable molecular drivers of chemotherapy resistance in gastroesophageal adenocarcinoma
Authors: Mingyang Kong, Swneke Bailey, Veena Sangwan, Lorenzo Ferri
Journal: Cancer Research (2022)

Abstract Introduction: Gastroesophageal adenocarcinoma (GEA) is one of the most lethal malignancies worldwide. Even with the standard-of-care chemotherapy, 40% of the patients are innately resistant and half of the initial responders develop acquired resistance. The molecular mechanisms underlying the development of resistance in GEA remain largely unknown. Methods: 30 GEA patients who received chemotherapy were included in this cohort. Both pre-and post-treatment primary tissues were collected to generate patient-derived organoids (PDOs). 29 PDOs were treated with chemotherapeutic agents and the cell viability was measured. We also evaluated the correlation between ex-vivo drug responses of PDOs and in-patient clinical responses. Data obtained from whole-exome (WES) and RNA sequencing of the primary tumor and their PDOs were analyzed to identify targetable molecules associated with chemo-resistance. Results: After treatment, the cell viability of the PDOs obtained from chemo-resistant patients was significantly higher than that of chemo-sensitive patients. The variant allele frequency of the PDOs recapitulated their parental tumors. WES of one patient tumor revealed an increased copy number of EGFR, and their PDOs showed high sensitivity to an EGFR inhibitor in the subsequent drug screens. Furthermore, 40% of chemo-sensitive patients had mutations in one or more genes belonging to the adhesion G protein-coupled receptors (GPCRs) family. The adenylate cyclase-activating G protein-coupled receptor signaling pathway was found to be significantly activated only in chemo-sensitive patients. Single-cell RNA sequencing of pre-and post-treatment tissue revealed a broadly shifted transcriptome in epithelial cells. Patients with upregulated cell stemness genes including CTNNB1, MYC, ETS2, and KLF4 had disease recurrence 6 months post-surgery, while patients with unaltered or downregulated stemness genes remain disease-free 18 months until today. Conclusion: Our PDOs not only reflected the genetic profile of primary tumors but also recapitulated patient responses to chemotherapy. Genomic analysis revealed that mutations in a few GPCR genes might have a role in increased sensitivity to chemotherapy. In addition, the transcriptomic analysis showed stemness genes were associated with disease recurrence. Our GEA PDO platform allows the identification and the subsequent verification of resistant-conferring targets, providing insight for novel therapeutic combinations. Funding: This project is supported by the Cancer Research Society (CCS), and the Department of Defence (DoD), USA. Citation Format: Mingyang Kong, Swneke Bailey, Veena Sangwan, Lorenzo Ferri. Identify targetable molecular drivers of chemotherapy resistance in gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3068.
Abstract 6182: A comprehensive panel of reporter cell lines to accelerate immune-checkpoint antibody discovery
Authors: Guoqian Wang, Zhengcheng Guo, Hongling Chen, Chang Liu, Jinying Ning, Feng Hao
Journal: Cancer Research (2022)

Abstract Anti-tumor immune therapy has achieved great success. Antibody drugs targeting PD1/PD-L1 have brought significant benefits for cancer patients. In the post-PD1/PD-L1 era, many novel targets for tumor-related immune modulation have been discovered, and tremendous efforts have been put to develop new biologics for these targets. There is an urgent need for a high-throughput functional system that mimics tumor immune microenvironment to screen antibodies. Equipped with expertise in tumor immunology and cell biology, KYinno has generated a panel of reporter cell lines to accelerate immune-checkpoint antibody discovery. The reporter system includes two types of engineered cell lines, one is CHO-K1 or 293T based aAPC (artificial antigen presenting cell) which provides both stimuli and inhibitor (ligand) signals, and the other one is Jurkat-NFAT-luciferase reporter cell line that over-expresses the drug target (receptor). In this co-culture system, the ligand-receptor complex can induce NFAT inhibitory signals. The functional antibodies can rescue the inhibitory signal by blockage of the ligand-receptor interaction. All the reporter cell lines have been well validated with benchmark antibodies. Currently, the systems cover immune modulation for TIGIT, LILRB1, LILRB2, PVRIG, Lag3, TIM3, NKG2a, NKp30, PD1, NKp46, etc. Citation Format: Guoqian Wang, Zhengcheng Guo, Hongling Chen, Chang Liu, Jinying Ning, Feng Hao. A comprehensive panel of reporter cell lines to accelerate immune-checkpoint antibody discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6182.
Abstract 2044: The target antigen determines the mechanism of acquired resistance to T cell based therapies
Authors: Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius, Marta Escorihuela, Antonio Luque, Irene Chicote, Hector García Palmer, Marina Bacac, Joaquin Arribas, Enrique Javier Arenas Lahuerta
Journal: Cancer Research (2022)

Abstract Introduction: Immunotherapy has revolutionized the way many cancers are treated. Despite its success, cancer patients eventually progress due to the emergence of resistance. In this scenario, the selection of the tumor antigen is important and can be decisive in the success of the clinical response, particularly when resistance emerge. T cell bispecific antibodies (TCBs) are engineered molecules that include, within a single entity, binding sites to the T cell receptor and to a tumor-specific or a tumor-associated antigen. It is assumed that, as all TCBs have the same mechanism of action, mechanisms of resistance are independent of the tumor antigen. Objective: This study was designed to identify the mechanisms that trigger the resistance against HER2 and CEACAM5 T cell bispecific antibodies. We assessed TCB sensitivity using in vitro and in vivo assays combining human cell lines or patient-derived models with human lymphocytes. Material and Methods: Using gastric CEA+/HER2+ MKN45 cells as a model and TCBs directed against CEA or HER2, here we show for the first time that the mechanism of resistance to a T cell-based therapy is dependent on the tumor antigen. Results: Acquired resistant models to a high-affinity CEA-targeted TCB exhibit a reduction of CEA antigen levels due to epigenetic transcriptional silencing, which is reversible upon 5-AZA treatment. In contrast, a HER2-TCB resistant model maintains HER2 levels as HER2 downregulation led to an impairment of proliferation. Furthermore, using this latter model, we identified that disruption of interferon- gamma signaling confers resistance to killing by active T lymphocytes. Conclusions: Our results unveil different mechanisms of acquired resistance to TCBs depending on the selected antigen, which will help in the design of combinatorial strategies to increase the efficacy of cancer immunotherapies and to anticipate and overcome resistances. Citation Format: Alex Martínez-Sabadell, Beatriz Morancho, Irene Rius, Marta Escorihuela, Antonio Luque, Irene Chicote, Hector García Palmer, Marina Bacac, Joaquin Arribas, Enrique Javier Arenas Lahuerta. The target antigen determines the mechanism of acquired resistance to T cell based therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2044.
Abstract 5904: The clinical, behavioral, and demographic factors associated with the quality of life of cancer survivors
Authors: Odette Chirinos, Eunkyung Lee
Journal: Cancer Research (2022)

Abstract The objective of this thesis is to assess the prevalence of low quality of life scores in adult cancer survivors. This thesis also intends to examine the predictors for low quality of life, separately for physical quality of life and mental quality of life. Possible predictors explored include diet quality, age at cancer diagnosis, race and ethnicity, body mass index, alcohol intake, physical activity, and more. The data source for this thesis is the National Health and Examination Survey 2005-2012. The sample population included 1244 cancer survivors 20 years or older that answered yes to the question “have you ever been told by a doctor or other health professional that had cancer or malignancy of any kind”? Both, mental and physical health, were determined based on the number of days physical and mental health was not good and dichotomized according to mean value. The four groups identified were low mental health and low physical health (n=148, 11.9%), low mental health and high physical health (n=239, 19.2%), high mental health and low physical health (n=143, 11.5%), and high mental health and high physical health (n=714, 57.4%). The diet quality was calculated using the Healthy Eating Index 2015 since it measures adherence to the Dietary Guidelines for Americans. The SAS Survey Analysis Procedures was used to account for the random multi-stage sampling of NHANES. On the other hand, ANOVA and chi-square were used to determine the possible predictors of low quality of life while multivariable logistic regression analysis was performed to examine the independent predictors of low physical and mental health with statistical significance was set at a two-sided p-value of &amp;lt;0.05. The results showed that age, economic status, and physical activity are predictors of low quality of life for adult cancer survivors. This indicates that future interventions for improving quality of life should be focused on increasing physical activity, especially in middle aged, obese, and economically disadvantaged cancer survivors. Citation Format: Odette Chirinos, Eunkyung Lee. The clinical, behavioral, and demographic factors associated with the quality of life of cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5904.
Abstract 1190: MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer
Authors: Dale A. Begley, Debbie M. Krupke, Steven Neuhauser, John Sundberg, Carol J. Bult
Journal: Cancer Research (2022)

Abstract The laboratory mouse is the premier mammalian model organism for interrogating the genetic and molecular basis of human cancer and for preclinical investigations into targets for the prevention and treatment of cancer. The distributed and heterogenous nature of information about these model systems makes it difficult for researchers to integrate and interpret the information to determine the state of the field and to identify the most relevant models for basic and preclinical research. The Mouse Models of Human Cancer database (http://tumor.informatics.jax.org) is an expertly curated knowledgebase about genetically defined mouse strains and Patient Derived Xenograft (PDX) models of human cancer. Data in MMHCdb are obtained from peer-reviewed scientific publications and direct data submissions from individual investigators and large-scale programs. MMHCdb is built on FAIR data management principles (Findable, Accessible, Interoperable, Reusable). The enforcement of metadata standards and official gene, allele and strain nomenclature ensure accurate and comprehensive search results for cancer models. MMHCdb has long represented data from spontaneous or endogenously induced tumors from genetically defined mice and for PDXs which have been the foundation of basic cancer research and preclinical studies for decades. MMHCdb has expanded to include cancer models such as Diversity Outbred and Collaborative Cross mice which are ideally suited for research into the relationship of genetic variation with cancer susceptibility and for modeling the genetics of variability in treatment responses. The MMHCdb contains over 109,266 curated tumor frequency records for over 8,275 mouse strains. Tumor types in the database have been indexed to over 21,000 literature citations. PDX models and data available in MMHCdb are also accessible from the Patient Derived Cancer Models resource at EMBL-EBI which currently provides information for over 4,000 PDXs (https://cancermodels.org).MMHCdb is supported by NCI R01 CA089713 Citation Format: Dale A. Begley, Debbie M. Krupke, Steven Neuhauser, John Sundberg, Carol J. Bult. MMHCdb: A knowledgebase for the evolving landscape of mouse models of human cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1190.
Abstract 849: Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome
Authors: Pamela Psarianos, Nicholas Fischer, Camilla Giovino, Noel Ong, David Malkin
Journal: Cancer Research (2022)

Abstract PURPOSE: Li-Fraumeni Syndrome (LFS) is a genetic disorder associated with a significant risk of early-onset cancer. This condition is largely driven by germline mutations in the TP53 tumor suppressor, which has a broad spectrum of functions including the transcriptional regulation of radiation response. Termed the guardian of the genome, TP53 serves as a critical checkpoint which coordinates DNA repair, cell cycle progression and apoptosis following DNA damage, ultimately controlling the fate of the cell. Aberrant or deficient TP53 function, such as occurs in LFS, contributes to radiation vulnerability. As a result, there is particular caution in the use of radiotherapy to treat primary LFS tumors, in order to prevent the formation of secondary, radiation-induced malignancies. To this end, therapeutic options for LFS are often limited to surgery and chemotherapy, posing substantial constraints for the treatment of patients who may otherwise benefit from primary tumor radiation. Metformin, a commonly prescribed anti-diabetic drug, is associated with lower cancer incidence in populations worldwide. Recent studies have shed light on the potential utility of metformin as a pharmacopreventive agent for primary tumors in LFS; hence, we hypothesize that the utility of metformin can be extended to the prevention of secondary malignancies following radiotherapy in LFS. METHODS/RESULTS: To explore the chemopreventive potential of metformin in LFS, we completed tumor challenges using a p53R172H/+ LFS mouse model. Mice treated prophylactically with metformin showed slower xenograft tumor growth compared to vehicle-treated mice. Ongoing work in our lab aims to characterize the effects of metformin on tumor growth following the administration of localized ionizing radiation (IR) to LFS mice. Briefly, these mice are treated with either vehicle or metformin, and IR is administered to the left hindlimbs to induce tumor formation. The timing and rates of tumor growth are monitored using magnetic resonance imaging. At endpoint, excised tumors are subjected to global profiling via RNA sequencing, proteomic analysis, and single-cell sequencing of discrete cell populations to characterize the effects of metformin on the development of radiation-induced malignancies. Results of these studies will be presented. SIGNIFICANCE: Overall, this work will advance our understanding of the chemopreventive effects of metformin, with the potential to broaden the treatment options available to LFS patients. Citation Format: Pamela Psarianos, Nicholas Fischer, Camilla Giovino, Noel Ong, David Malkin. Characterization and prevention of radiation-induced malignancies in Li-Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 849.
Abstract 4244: Using lysosomal immunogenic cell death to target cancer via xanthine oxidase
Authors: Iulianna Taritsa, Eric Fossel, Kuldeep Neote
Journal: Cancer Research (2022)

Abstract Lysosome-induced immunogenic cell death (LIICD) is a powerful mechanism of targeting cancer cells that kills circulating malignant cells and primes the host’s immune cells against future remission. Current immunotherapies for cancer are limited in preventing recurrence - a gap which can be bridged by training the immune system to recognize cancer neoantigens. Lysosomal leakage can be induced therapeutically to traffic antigens from dying cells to dendritic cells which can later present those tumorigenic antigens to T cells. We demonstrate that the oxidative agent native bovine xanthine oxidase can induce early markers of lysosome-induced immunogenic cell death in an in vitro human cancer cell line (CCL2). Specifically, we measured overall cell death, as well as surface-expressed calreticulin, extracellular ATP release, and HMGB1 production. These markers are consensus indicators of ICD. Flow cytometry, luminescence assays, and ELISA were used respectively to quantify biomarker levels between treated versus untreated cells. We also included a positive control group of cells dosed with doxorubicin (a known inducer of LIICD). We looked at each marker at various time points after cancer cells were treated with xanthine oxidase, doxorubicin, and an untreated group. Upregulated biomarkers after treatment with the protein indicate an immunogenic response. Further, we used confocal imaging to show lysosomal membrane permeabilization after treatment with Native Bovine Xanthine Oxidase using Lucifer Yellow staining. We thus show the potential for this protein to induce an anticancer effect paired with an adaptive immune response against tumor cells. Our research in human cell lines here provides evidence for the success of the same therapeutic method in patients and serve as the gateway to developing a new treatment approach against breast cancer. Citation Format: Iulianna Taritsa, Eric Fossel, Kuldeep Neote. Using lysosomal immunogenic cell death to target cancer via xanthine oxidase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4244.
Monkeypox Genital Lesions
Authors: Rita Patrocinio-Jesus, Francesca Peruzzu
Journal: New England Journal of Medicine (2022)

A 31-year-old man with well-controlled infection with the human immunodeficiency virus presented to the clinic with a 1-week history of a painless genital rash and a 2-day history of fever and sore throat.Three weeks earlier, he had had condomless intercourse with a new male partner.On physical examination, a macular rash and painful lymphadenopathy were observed in the right inguinal area (Panel A), and two ulcerated lesions and several umbilicated pustules were observed on the penis (Panel B).Tests for syphilis, chlamydia, and gonorrhea were negative.Antimicrobial therapy for possible lymphogranuloma venereum and chancroid was initiated.Five days after the initial presentation, the patient returned with vesiculopustular lesions on the face and hands.Polymerase-chain-reaction assays of swabs obtained from lesions on the genitals and the hands were positive for monkeypox.In classic cases of monkeypox, patients have a febrile prodrome followed by a rash that may appear on any part of the body, with lesions that evolve simultaneously.In the current global outbreak of monkeypox, painless anogenital lesions -often without a prodrome -are being observed in persons who have had close contact with an infected person or persons, including men who have sex with men.Within 2 weeks after his initial presentation, the patient's lesions had abated without specific intervention.Additional examples of monkeypox genital lesions that were observed in other patients are shown in Panels C and D.